The continued rise in annual pancreatic cancer mortalities demands urgent efforts to better understand molecular mechanisms critical to tumor progression and therapeutic resistance. Our group and others identified the RON tyrosine kinase receptor as an overexpressed protein and potential novel therapeutic target in pancreatic cancer. The working hypothesis of our laboratory is that RON receptor signaling is a potent promoter of invasive growth and survival in human pancreatic cancer cells which uniquely also helps to shape the tumor microenvironment via its effects on myeloid cell function. Our recent studies demonstrate that RON signaling accelerates pancreatic duct neoplasia initiated by KRAS and that RON signaling in pancreatic cancer cells initiates a positive feedback loop driving expression of both RON itself and its cognate ligand, macrophage stimulating protein. We believe that RON signaling thereby serves to modify both epithelial and immune cell phenotypes to promote tumor growth, metastasis and therapeutic resistance. The goals of this application are; 1) to understand how autocrine/paracrine RON signaling influences primary pancreatic cancer growth, 2) determine the mechanisms by which RON signaling modifies the primary and metastatic niche to promote tumor dissemination and metastatic outgrowth, and 3) to test RON inhibition as an immunomodulatory strategy in preclinical models of pancreatic cancer. The findings from these studies will enhance our understanding of RON biology and thereby serve to inform the development and further testing of RON- directed therapies in pancreatic cancer.